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Signals transduced by the B cell antigen receptor (BCR) are essential for B cell development and activation. Precise regulation of BCR signals is required to provide antigenspecific humoral immunity on one hand and tolerance of self proteins on the other hand. The SH2 domain-containing inositol 5' phosphatase (SHIP) is an important component for limiting antigen-induced signals in B cells. SHIP hydrolyzes the 5' phosphate of phosphatidyl-3,4,5trisphosphate (PIP3) at the inner leaflet of the plasma membrane thereby disrupting binding motifs for the plextrine homology domains and attenuating the activities of Bruton's tyrosine kinase and phospholipase C-γ (PLC-γ2), respectively. Initially SHIP activation was believed to depend on inhibitory coreceptors like the Fc-γRIIB. However, studies using ship-/- DT40 cells or mice revealed that SHIP is activated downstream of BCR engagement in absence of Fcγ-RIIb also. The mechanism of BCR-induced SHIP activation and its relocalization towards the substrate PIP3, however, remains obscure to date. Here we report a real time imaging approach to analyze the molecular mechanism of BCR-induced SHIP relocalization. Interestingly, neither Fcg-RIIb nor the SHIP SH2 domain contributed to this process. Using genetic variants of DT40 B cells we could show that SHIP plasma membrane recruitment occurs upstream of PLC-γ2 activation. Our studies revealed that two apparently independent mechanisms are involved. First the Lyn-dependent assembly of a trimolecular complex comprising SHIP, the SH2 domaincontaing adapter protein (Shc) and the growth factor receptor-bound protein 2 (Grb2) supports the SHIP relo-